Caffeine for Sedation Recovery in Children

Overseen By Zheng Xie, MD, PhD

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: University of Chicago

Disqualifiers: Arrhythmia, Congenital heart disease, others

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Dexmedetomidine (Dex), a selective α2-adrenergic receptor agonist, is the most used sedative for procedural sedation in children and in pediatric Intensive Care Unit (PICU) because it is associated with less respiratory depression and also less neurotoxicity; rather Dex appears neuroprotective. Unfortunately, Dex is associated with very long emergence times and may cause bradycardia and hypotension. However, using sedation dosing guidelines (by consensus among SPS members) 1-3 mcg/kg bolus and a 1-2 mcg/kg/hour infusion, hemodynamic compromise is less significant and rarely requires intervention in these patients. With this Dex sedation protocol, these pediatric patients usually take an average of 45 minutes (30-60 minutes) to wake and become alert and up to 2 hours to be discharged. Without reversal agents, emergence times from Dex sedation are slow. The prolonged recovery after Dex sedation for non-surgical procedures negatively affects throughput, thus increasing the cost of care. Patient safety and satisfaction suffer as a result. The children wake feeling tired and sluggish. The children don't feel back to normal for an extended period of time, which is not surprising given that the half-life for Dex metabolism in 2-3 hours in humans. However, using sedation dosing guidelines (by consensus among SPS members) 1-3 mcg/kg bolus and a 1-2 mcg/kg/hour infusion, hemodynamic compromise is less significant and rarely requires intervention in these patients. In humans, it has been found that caffeine at 7.5 mg/kg (15 mg caffeine citrate equivalent to 7.5 mg caffeine base) sped emergence from isoflurane anesthesia with minimal hemodynamic effects in healthy human volunteers. The goal of this clinical trial is to determine whether caffeine will facilitate the recovery of Dex sedation after a Magnetic Resonance Imaging (MRI) procedure by measuring the time from the end of Dex infusion to the time meeting the discharge criteria.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of caffeine as a drug for sedation recovery in children?

Research shows that caffeine, when combined with other pain relievers, can enhance pain relief, as seen in studies on tension-type headaches and other pain conditions. This suggests caffeine may have beneficial effects in other contexts, such as aiding recovery from sedation. ^{1 2 3 4 5}

Is caffeine safe for use in humans?

Research shows that caffeine, when combined with other medications like paracetamol or ibuprofen, is generally safe for treating headaches, with no significant difference in safety compared to other treatments. Common side effects are mild and may include dizziness or nausea. ^{1 4 6 7 8}

How does caffeine differ from other drugs for sedation recovery in children?

Caffeine is unique for sedation recovery in children because it is not a traditional sedative or pain medication; instead, it acts as a stimulant that can help counteract the sedative effects by increasing alertness and reducing recovery time. This approach is different from typical sedative reversal agents, which often work by directly counteracting the sedative's effects on the brain. ^{1 2 9 10 11}

Research Team

Zheng Xie, MD,PhD

Principal Investigator

University of Chicago

Eligibility Criteria

This trial is for pediatric patients who have undergone fast-track surgery and received Dexmedetomidine sedation during an MRI. They must be suitable for receiving caffeine as a potential recovery aid post-MRI.

Inclusion Criteria

My weight is 33.3 kg or less.

My gender does not affect my eligibility.

No prior history of difficulty with anesthesia

Exclusion Criteria

History of head trauma

I have a history of heart, liver, or kidney diseases.

I weigh more than 33.3 kg.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-3 days

1 visit (in-person or virtual)

Pre-sedation

Patient arrives in sedation suite, vitals obtained, and sedation plan reviewed

Same day as MRI

1 visit (in-person)

Sedation

Induction with Dexmedetomidine and monitoring during MRI procedure

Approximately 1-2 hours

1 visit (in-person)

Recovery

Patient receives study drug (caffeine or placebo) and is monitored until discharge criteria are met

Up to 2 hours

1 visit (in-person)

Follow-up

Patient receives follow-up call to assess recovery and satisfaction

1 day

1 call (virtual)

Treatment Details

Interventions

• Caffeine (Other)

Trial Overview The study tests if caffeine can speed up recovery from sedation with Dexmedetomidine in children after an MRI. It measures the time to wake up and meet discharge criteria compared to usual care without caffeine.

Participant Groups

Group I: Dexmedetomidine +/- Caffeine Sedation Experimental Treatment 1 Intervention

Eligible subjects will be given 10 mg/kg caffeine citrate (equivalent to \~5 mg/ kg caffeine base) \~ 15 min after terminating Dex's infusion.

Group II: Dexmedetomidine +/- Placebo Sedation Placebo Group 1 Intervention

Eligible subjects will be given 9 mg/ml saline placebo) \~ 15 min after terminating Dex's infusion.

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Findings from Research

The combination of paracetamol (1,000 mg) and caffeine (130 mg) (PCF) was found to be well-tolerated and effective for treating tension-type headache (TTH) in an Italian population, based on a multicenter, randomized, double-blind, placebo-controlled trial.

Both PCF and naproxen sodium (550 mg) showed significant efficacy compared to placebo, but there was no significant difference in effectiveness between PCF and naproxen, indicating that PCF is a viable alternative for acute TTH treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium. Pini, LA., Del Bene, E., Zanchin, G., et al.[2018]

In a study involving 60 young, healthy volunteers, tramadol, dextropropoxyphene, and a commercial drug mixture all significantly increased pain thresholds in dental pulp, indicating their analgesic efficacy.

There was no significant difference in the pain-relieving effects among the three drugs, suggesting that they may be equally effective for managing pain in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effect of tramadol and other analgesics on the pain threshold in human dental pulp (author's transl)]. Rost, A., Schenck, EG.[2006]

In a study evaluating pain relief after wisdom tooth surgery, combinations of hydrocodone-acetaminophen and codeine-acetaminophen were found to be effective for managing moderate to severe pain, showing significant analgesic effects compared to placebo.

All active medications provided similar levels of pain relief, and any adverse effects experienced were temporary and primarily linked to the central nervous system effects of the medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the analgesic efficacy of three opioid-analgesic combinations in postoperative oral surgery pain. Forbes, JA., Bowser, MW., Calderazzo, JP., et al.[2020]

In a study involving 1743 patients, the fixed combination of acetylsalicylic acid, paracetamol, and caffeine (Thomapyrin) provided significantly faster pain relief for tension-type headaches and migraines compared to other treatments, including placebo and individual components.

All treatments were well tolerated with a low incidence of adverse events, indicating that the combination therapy is not only effective but also safe for patients accustomed to using non-prescription analgesics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Diener, HC., Pfaffenrath, V., Pageler, L., et al.[2013]

Thomapyrin, a popular over-the-counter analgesic in Germany for 50 years, combines acetylsalicylic acid, paracetamol, and caffeine, demonstrating a 1.4-fold increase in analgesic effectiveness due to the synergistic effects of its ingredients.

The combination does not alter the side effect profile compared to individual components, indicating a favorable benefit/risk ratio, making it suitable for self-medication in managing various types of pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effectiveness of fixed analgesic combinations exemplified by thomapyrin]. Aicher, B., Kraupp, O.[2013]

In phase 3 trials, sumatriptan/naproxen sodium (Treximet®) was found to be significantly more effective than placebo in providing pain relief for migraines in both adolescents and adults, with a notable increase in the number of patients who were pain-free at 2 hours after treatment.

The combination medication was generally well tolerated, with low rates of treatment-related adverse events (≤11% in adolescents and ≤22% in adults), making it a safe and effective option for acute migraine treatment that may also enhance patient adherence due to its fixed-dose formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sumatriptan/Naproxen Sodium: A Review in Migraine. Syed, YY.[2018]

In a multi-center randomized controlled trial involving migraine patients, the combination of paracetamol (1,000 mg) and caffeine (130 mg) was found to be as effective as sumatriptan (50 mg) in relieving migraine pain.

Both treatments showed similar tolerability, with no significant differences in adverse events reported, confirming that the combination of paracetamol and caffeine is a safe alternative for migraine relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of tolerability and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of migraine attack: a randomized, double-blind, double-dummy, cross-over study. Pini, LA., Guerzoni, S., Cainazzo, M., et al.[2021]

A multicenter, double-blind, placebo-controlled trial was conducted to evaluate the effectiveness and safety of combining ibuprofen with caffeine for treating tension-type headaches, building on previous evidence of caffeine's analgesic properties.

The study aims to confirm the pain-relieving effects of caffeine and explore how tension-type headaches can serve as a useful model for pain research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of ibuprofen plus caffeine to treat tension-type headache. Diamond, S., Freitag, FG.[2019]

The combination of indomethacin, caffeine, and prochlorperazine (IndoProCaf) effectively reverses hyperalgesia in mice, demonstrating a significant increase in pain threshold after treatment, even at doses much lower than typical analgesics.

IndoProCaf showed superior efficacy in reducing pain compared to the individual components, indicating that the combination therapy may be particularly effective for conditions like migraine, where hyperalgesia is present.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine. Galeotti, N., Ghelardini, C., Grazioli, I., et al.[2019]

Codeine has seen a significant decline in use for managing moderate to severe pain in children due to safety concerns, leading to a search for alternative opioids.

Oral morphine is currently the most well-supported alternative to codeine for children, with more evidence of its safety and efficacy, while further research is needed on other opioids and non-opioid pain management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of oral opioids to control children's pain in the post-codeine era. Rieder, MJ., Jong, G'.[2022]

The fixed combination of indomethacin, prochlorperazine, and caffeine (Difmetré®) has been shown to be effective and well tolerated for treating migraine and episodic tension-type headache in adult patients, based on randomized, multicenter studies.

Rectal formulations of this combination were found to be significantly more effective than sumatriptan for migraine treatment, while oral formulations showed similar efficacy to sumatriptan and nimesulide, providing additional options for acute headache management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indomethacin/prochlorperazine/caffeine: a review of its use in the acute treatment of migraine and in the treatment of episodic tension-type headache. Hoy, SM., Scott, LJ.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

[The effect of tramadol and other analgesics on the pain threshold in human dental pulp (author's transl)]. [2006]

3. United States pubmed.ncbi.nlm.nih.gov

An evaluation of the analgesic efficacy of three opioid-analgesic combinations in postoperative oral surgery pain. [2020]

4. England pubmed.ncbi.nlm.nih.gov

The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. [2013]

5. Austria pubmed.ncbi.nlm.nih.gov

[Effectiveness of fixed analgesic combinations exemplified by thomapyrin]. [2013]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Sumatriptan/Naproxen Sodium: A Review in Migraine. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Comparison of tolerability and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of migraine attack: a randomized, double-blind, double-dummy, cross-over study. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

The use of ibuprofen plus caffeine to treat tension-type headache. [2019]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine. [2019]

10. England pubmed.ncbi.nlm.nih.gov

The use of oral opioids to control children's pain in the post-codeine era. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Indomethacin/prochlorperazine/caffeine: a review of its use in the acute treatment of migraine and in the treatment of episodic tension-type headache. [2021]